Background: Allogeneic stem cell transplantation (alloSCT) is a potentially curative treatment for several hematologic disorders, and involves donation of human leukocyte antigen (HLA)-matched stem cells to the recipient. In an effort to obtain the highest degree of HLA-match, given the improved survival and decreased risk of graft-versus-host disease (GVHD), patients may receive stem cells from a donor who is ABO-mismatched. Recipients of ABO-mismatched transplants are at increased risk of long-term complications such as pure red cell aplasia (PRCA). PRCA is suspected when patients develop transfusion dependence in the setting of hypoproliferative anemia, and can be confirmed by the absence of erythroid progenitors in the bone marrow. Management of PRCA is not standardized and is largely based on guidance from expert panels and case series. Recently, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has been explored as a possible effective, oral therapy for PRCA. We report on our center's experience with the use of ibrutinib for PRCA.

Methods: Seventeen patients with PRCA following alloSCT were identified and reviewed under IRB approval. PRCA was diagnosed based on the need for frequent transfusions in the setting of hypoproliferative anemia, or based on erythroid hypoplasia on bone marrow biopsy.

Results: Among identified patients, indications for transplant included: AML, MDS, MF, AMML, CMML, CTCL and MCL. All but one patient received a peripheral blood stem cell source, with one receiving a bone marrow source. Seventy-one percent (n=12) had a matched unrelated donor, 12% (n=2) had a matched sibling donor, 12% (n=2) had a haploidentical donor, and one patient had a mismatched unrelated donor. Eighty-two (n=14) percent of patients received reduced-intensity conditioning while 18% received myeloablative conditioning, and 76% (n=13) received calcineurin inhibitor-based GVHD prophylaxis while 14% received a post-transplant cyclophosphamide regimen. All (n=17) recipients had O+ blood type. Eighty-two percent (n=14) of donors had A+ blood type, 12% (n=2) had B+ blood type, and 6% (n=1) had AB- blood type.

Of the 17 patients, 59% (n=10) were treated with ibrutinib. Of these 10 patients, 90% (n=9) were treated with 420mg daily or the dose-adjusted equivalent due to concomitant drug interactions; one patient was ultimately dose-reduced due to cytopenias. Forty percent (n=4) were treated first line, 30% (n=3) second line, and the remaining 30% (n=3) were treated 3rd-6th line. Among patients who had received prior therapies (n=6), treatment included rituximab (100%), stem cell boost (33%), intravenous immunoglobulin (IVIG; 33%), high-dose prednisone (17%), bortezomib (17%), and daratumumab (17%). Median time to initiation of ibrutinib was 163 days (range 60-487).

Median hemoglobin prior to initiation of ibrutinib was 7.8g/dL, 7.9g/dL at 30 days post-initiation, 8.9g/dL at 60 days post-initiation, and 9.9 g/dL at the date of discontinuation. The median number of RBC transfusions 30 days prior to therapy was 4 units, 2 units at 30 days post-initiation, and 1.5 units at 60 days post-initiation. Seventy percent (n=7) of patients achieved transfusion independence, with median time to independence being 47 days.

The median duration of therapy was 83 days. Half (n=5) of the patients discontinued therapy due to neutropenia. Two patients discontinued therapy due to lack of response; one in the setting of concurrent use with azacitidine maintenance post-transplant, and the other in the setting of first-line ibrutinib use 64 days post-transplant. Of the 3 patients who did not achieve transfusion independence, one patient was 20 days into their active ibrutinib course while the other 2 patients went on to receive subsequent therapies due to lack of response, in the aforementioned clinical settings.

Discussion: Overall, the use of ibrutinib for PRCA following an ABO-mismatched alloSCT can provide an effective, oral option for patients. We found that median hemoglobin values improved over the 30 and 60 days post-initiation of therapy, and median monthly transfusion needs decreased. Despite half of patients discontinuing therapy due to neutropenia, 70% of patients had resolution of PRCA and achieved transfusion independence following treatment with ibrutinib. Forty percent of patients received ibrutinib as first line of therapy for PRCA, and future studies are needed to further explore optimal timing of therapy.

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2025
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